Smoking, ethamphetamine (meth), and alcohol use remain a significant health burden. Notably, clinical studies have identified sex differences in response and sensitivity to the drugs, as well as in abstinence and relapse rates. Interestingly, preclinical investigations on these topics have not been as prevalent. There is an extensive literature establishing that stimuli associated with drugs can be powerful modulators of drug-seeking behavior, and can promote relapse following a period of abstinence. One factor of importance to the development and tenacity of nicotine dependence is the ability of the pharmacological effects of nicotine to serve as an interoceptive stimulus for other reinforcing events (e.g., peer acceptance, alcohol, work breaks, stress relief, etc.). Consequently, over time a smoker has an opportunity to develop a rich appetitive conditioning history with the interoceptive stimulus effects of nicotine. An important prediction from theories of conditioned reinforcement and incentive motivation is that an excitatory conditioned stimulus, nicotine in our case, should be able to support other behavior. Using preclinical models, one goal of the present application is to directly test the hypothesis that following an appetitive interoceptive conditioning history with nicotine, the nicotine stimulus will acquire additional motivational valu that will exacerbate reinstatement of methamphetamine (Aim 1) and alcohol (Aim 2) seeking to a greater degree than not having this conditioning history. Another goal is to determine whether sex differences exist in these behaviors. The proposed studies will fill an important gap in the literature, as it is unknown whether interoceptive conditioning involving a drug stimulus can alter the extent of reinstatement that had been maintained by a different drug. This is an innovative conceptual framework by which to approach the subject of relapse in addiction. Accordingly, confirmation of this hypothesis will advance current theory as it reveals a potential new process that may serve as a risk factor in relapse. Opening a new area of scientific inquiry, advancement of theory, and improvement of animal models are consistent with the objectives of the R21 mechanism - Exploratory/Developmental Research Grant Award.